ECEESPE2025 Oral Communications Oral Communications 4: Pituitary, Neuroendocrinology and Puberty Part 1 (6 abstracts)
Differential temporal onset of kisspeptin action following intranasal and intravenous administration supports a novel human olfactory-reproductive pathway
Jovanna Tsoutsouki 1 , Edouard G Mills 1,2 , Maria Phylactou 1,2 , Sophie Clarke 1 , Layla Thurston 1 , Lisa Yang 1 , Bijal Patel 1 , Pei Eng 1 , Chioma Izzi-Engbeaya 1,2 , Emma Alexander 1 , Muhammad Choudhury 1 , Paul Bech 1 , Magda Swedrowska 3 , Ben Forbes 3 , Ali Abbara 1 , Alexander Comninos 1,2 & Waljit Dhillo 1
1Imperial College London, Department of Metabolism, Digestion and Reproduction, London, United Kingdom; 2Imperial College Healthcare NHS Trust, Department of Endocrinology, London, United Kingdom; 3Institute of Pharmaceutical Science, King’s College London, London, United Kingdom
JOINT206
Background: The most characterised pathway for kisspeptin’s activation of the reproductive axis involves the stimulation of kisspeptin receptors on GnRH neurones within the hypothalamus. However, recent rodent evidence reveals an extra-hypothalamic population of GnRH neurons in the olfactory bulb that also express kisspeptin receptors. Intranasal kisspeptin administration could directly activate these olfactory bulb-GnRH neurones, triggering reproductive hormone release and unveiling a novel olfactory-reproductive pathway. Herein, we compare the reproductive hormone responses to intranasal and intravenous kisspeptin administration in humans for the first time, providing mechanistic insights and highlighting a non-invasive clinical route of kisspeptin administration.
Methods: Healthy male participants received 12.8 nmol/kg of kisspeptin-54 via either intranasal delivery (n=12) or intravenous bolus injection (n=5). Reproductive hormone levels were measured at 15 minute intervals over 6 hours following administration. The mean maximum increase in reproductive hormones from baseline and the median time to peak response between the two groups were analysed using an unpaired t-test and Mann-Whitney test, respectively.
Results: Both intranasal and intravenous kisspeptin-54 elicited significant gonadotrophin and testosterone responses. Although the peak LH response was lower with intranasal, compared to intravenous, administration (mean±SEM [IU/l]: 4.5±0.6 above baseline for intranasal vs. 11.3±1.4 for intravenous, P<0.0001), intranasal kisspeptin-54 induced a notably earlier LH peak, with a median time of 38 minutes, compared to 300 minutes for intravenous administration (P=0.0002). Similar patterns were observed for FSH, with a peak (mean±SEM [IU/l]) of 0.7±0.2 above baseline at 38 minutes (IQR: 30–79) following intranasal administration, compared to 2.3±0.22 above baseline at 345 minutes (IQR: 345–360) following intravenous kisspeptin-54 (P=0.0003 for magnitude, P=0.0002 for timing). The peak testosterone responses did not differ significantly following intranasal and intravenous kisspeptin-54 (P=0.1864), but the median peak was attained earlier following intranasal administration (165 minutes; IQR: 109–240), compared to intravenous administration (345 minutes; IQR: 240–360, P=0.0116). Neither intranasal nor intravenous kisspeptin-54 administration were associated with any adverse effects.DiscussionThe remarkably faster onset of reproductive hormone responses following intranasal compared to intravenous kisspeptin-54 suggests that this route leverages a direct olfactory-reproductive pathway mediated by kisspeptin receptors on olfactory GnRH neurones. These findings have significant clinical implications for the therapeutic use of kisspeptin for common reproductive and psychosexual disorders, whilst also providing evidence for a newly identified kisspeptin mediated olfactory-reproductive pathway in humans.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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